Cathepsin G degradation of phospholipid transfer protein (PLTP) augments pulmonary inflammation

Anthony Brehm, Patrick Geraghty, Michael Campos, Itsaso Garcia-Arcos, Abdoulaye Jules Dabo, Adam Gaffney, Edward Eden, Xian Cheng Jiang, Jeanine D'Armiento, Robert Foronjy

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Phospholipid transfer protein (PLTP) regulates phospholipid transport in the circulation and is highly expressed within the lung epithelium, where it is secreted into the alveolar space. Since PLTP expression is increased in chronic obstructive pulmonary disease (COPD), this study aimed to determine how PLTP affects lung signaling and inflammation. Despite its increased expression, PLTP activity decreased by 80% in COPD bronchoalveolar lavage fluid (BALF) due to serine protease cleavage, primarily by cathepsin G. Likewise, PLTP BALF activity levels decreased by 20 and 40% in smoke-exposed mice and in the media of smoke-treated small airway epithelial (SAE) cells, respectively. To assess how PLTP affected inflammatory responses in a lung injury model, PLTP siRNA or recombinant protein was administered to the lungs of mice prior to LPS challenge. Silencing PLTP at baseline caused a 68% increase in inflammatory cell infiltration, a 120 and 340% increase in ERK and NF-κB activation, and increased MMP-9, IL1β, and IFN-γ levels after LPS treatment by 39, 140, and 190%, respectively. Conversely, PLTP protein administration countered these effects in this model. Thus, these findings establish a novel anti-inflammatory function of PLTP in the lung and suggest that proteolytic cleavage of PLTP by cathepsin G may enhance the injurious inflammatory responses that occur in COPD.

Original languageEnglish (US)
Pages (from-to)2318-2331
Number of pages14
JournalFASEB Journal
Volume28
Issue number5
DOIs
StatePublished - May 2014

Keywords

  • Lipopolysaccharide
  • Lung
  • Protease
  • Signaling

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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